WO2010043446A2 - Préparations pour une libération contrôlée de principes actifs - Google Patents

Préparations pour une libération contrôlée de principes actifs Download PDF

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Publication number
WO2010043446A2
WO2010043446A2 PCT/EP2009/061379 EP2009061379W WO2010043446A2 WO 2010043446 A2 WO2010043446 A2 WO 2010043446A2 EP 2009061379 W EP2009061379 W EP 2009061379W WO 2010043446 A2 WO2010043446 A2 WO 2010043446A2
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preparation according
polymer
range
acid
preparation
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PCT/EP2009/061379
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German (de)
English (en)
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WO2010043446A3 (fr
Inventor
Geoffrey Hills
Saskia KLEE-LAQUAI
Peter Lersch
Mike Farwick
Axel Kobus
Matthias Seiler
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Evonik Goldschmidt Gmbh
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Publication of WO2010043446A2 publication Critical patent/WO2010043446A2/fr
Publication of WO2010043446A3 publication Critical patent/WO2010043446A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K40/00—Shaping or working-up of animal feeding-stuffs
    • A23K40/30—Shaping or working-up of animal feeding-stuffs by encapsulating; by coating
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
    • A23L27/70—Fixation, conservation, or encapsulation of flavouring agents
    • A23L27/72—Encapsulation
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/175—Amino acids
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/18—Peptides; Protein hydrolysates
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P10/00—Shaping or working of foodstuffs characterised by the products
    • A23P10/30—Encapsulation of particles, e.g. foodstuff additives
    • A23P10/35—Encapsulation of particles, e.g. foodstuff additives with oils, lipids, monoglycerides or diglycerides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/11—Encapsulated compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/37—Esters of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/85—Polyesters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B01J13/04—Making microcapsules or microballoons by physical processes, e.g. drying, spraying
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/41—Particular ingredients further characterized by their size
    • A61K2800/412—Microsized, i.e. having sizes between 0.1 and 100 microns
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q15/00—Anti-perspirants or body deodorants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A61Q5/06—Preparations for styling the hair, e.g. by temporary shaping or colouring

Definitions

  • the present invention relates to controlled-release preparations of active substances and to methods for producing and using these preparations.
  • bioactive natural substances such as plant extracts, vitamins or oils containing a high proportion of unsaturated fatty acids
  • these storage conditions can often be met only to a very limited extent. For this reason, many of these substances are converted into preparations that allow easy storage. Furthermore, these preparations often allow targeted release of these drugs at a designated location or over a period of time.
  • these preparations are widely described as encapsulated systems comprising an active agent and an encapsulating material which exerts a protective function or through whose properties the release profile can be selectively controlled.
  • hyperbranched polymers are often used as the encapsulation material.
  • the use of hyperbranched polymers as a carrier for medicaments is set forth, for example, in WO 2004/072153.
  • the carrier molecule enables a sustained release and a facilitated transport of the drugs into the cells.
  • modified dendrimers are presented which have groups comprising nitrogen.
  • the document WO 00/065024 describes polymers for the encapsulation of hydrophobic molecules.
  • a plurality of hydrophobic residues is bound to a polyol core, wherein the resulting polymer is then reacted by polyalkylene oxides to obtain a water-soluble polymer.
  • compositions comprising a hyperbranched polymer which is coupled to a biologically active radical.
  • hyperbranched polymers in particular polyamidoamines or polypropylene amines are set forth.
  • hyperbranched polymers are described in the publication WO 00/06267, in particular polyetherimides being presented as hyperbranched polymers.
  • dendritic polymers preparations comprising dendritic polymers and pharmaceutically active agents are set forth in WO 03/033027, wherein the dendrimer comprises cationic groups.
  • hyperbranched polymers are provided with ionic groups.
  • US Pat. Nos. 6,379,683 and EP 1 034 839 B1 describe nanocapsules which have hyperbranched polymers.
  • the disadvantage here is in particular that the nanocapsules can not be isolated from the dispersion and further processed.
  • organic solvents are used to prepare the nanocapsules, which can not be completely removed from the dispersion in many cases.
  • compositions comprising hyperbranched polymers are further set forth in US 2006/0030686.
  • these polymers serve in particular as Formulation auxiliaries.
  • preparations that allow controlled release of drug are not described.
  • Active ingredients is achieved, for example, the subject of WO 2006/047714.
  • these preparations comprise an active ingredient covalently bonded to a polymer or oligomer.
  • the release of the active ingredient is effected in particular by an enzymatic cleavage of this covalent bond.
  • the active ingredient can advantageously be released in a targeted manner at a predetermined site of action.
  • a disadvantage of these systems is that the active substance must first be bound to a polymer. This restricts the application of this method. Furthermore, this will only insignificantly improve the shelf life of the active ingredients.
  • natural active ingredient combinations such as plant extracts are very difficult to be converted in natural composition in a corresponding preparation.
  • the property profile includes in particular the control possibilities of the release of active substance.
  • the preparations according to the invention should be able to release the active substance in a selected medium over as long a period as possible, wherein the release rate should preferably remain constant.
  • the release should be targeted within a short period of time.
  • an object can be seen in providing a preparation in which the release of the active ingredient can be controlled as simply and reliably as possible.
  • the preparation should show a particularly high stability, which in particular sensitive active ingredients can be stored over a particularly long period of time, without the properties of the active ingredient are significantly changed.
  • the preparations should also have a high shear stability, so that a simple and easy processing of the preparations is possible.
  • the present invention accordingly provides a preparation comprising an encapsulating material and at least one active substance, wherein the active ingredient can be released controlled from the preparation, which is characterized in that the encapsulating material at least one enzymatically degradable substance, excluding glycerides, having a melting point of at least 35 0 C and additionally comprises at least one polymer having polyester units, wherein the polymer having polyester units has a melting temperature of at least 30 0 C and a viscosity in the range of 50 mPa * s to 250 Pa * s, as measured by rotational viscosimetry at 110 0 C.
  • the encapsulating material at least one enzymatically degradable substance, excluding glycerides, having a melting point of at least 35 0 C and additionally comprises at least one polymer having polyester units, wherein the polymer having polyester units has a melting temperature of at least 30 0 C and a viscosity in the range of 50 mPa * s to 250 Pa * s,
  • the preparations according to the invention can have an excellent release profile of the active substance, it being possible to realize both a release over a particularly long period of time and a short-term release after actuation of a triggering mechanism.
  • preparations can have a high shear stability.
  • the preparations obtainable according to the invention can be processed in a particularly simple and trouble-free manner.
  • the preparations can be particularly easily adapted to specific needs.
  • preparations can have a wide variety of release mechanisms. These include mechanisms based on enzymatic degradation of the encapsulating material or pH-selective opening of the encapsulating material; Temperature- or solvent-controlled processes, action of energy on the preparations, for example irradiation of particles with electromagnetic
  • the preparations may have a high content of active ingredient.
  • the presently presented preparation allows a particularly stable storage of sensitive drugs. Accordingly, sensitive substances can be safely and easily stored.
  • the preparations according to the invention are surprisingly stable, so that they can be stored for a long period of time without degradation takes place. Furthermore, the preparations due to the high shear stability can be processed easily. A particular advantage results in particular from the fact that the preparations at room temperature, especially at 25 0 C, are solid, so that this solid can be incorporated into many end products without consuming and difficult to control process steps.
  • the preparations of the present invention can often be obtained in a particularly simple and cost-effective manner. Furthermore, the preparations according to the invention are harmless to health. It is particularly advantageous that the preparations according to the invention are obtainable without the use of organic solvents. Therefore, very natural preparations can be obtained which contain no residual organic solvents.
  • active ingredient refers to substances which produce a specific action in a small dose in an organism, for example, a pharmaceutical active ingredient is understood to mean, in particular, a substance which is intended to be used as an active ingredient in the manufacture of medicaments its use in the manufacture of medicines to become a pharmaceutically active ingredient.
  • encapsulating material refers in particular to a mixture comprising at least one enzymatically degradable substance, excluding glycerides, having a melting point of at least 35 ° C. and additionally comprising at least one polymer having polyester units, the polymer having
  • Polyester units have a melting temperature of at least 30 ° C and a viscosity in the range of 50 mPa * s to 250 Pa * s, as measured by rotational viscometry at 110 0 C having.
  • the enzymatically degradable substance and optionally the glyceride are not covalently bound to the polymer with polyester units.
  • enzymes in the context of the present invention refers to any enzymatically degradable substances and, although not explicitly mentioned, removes glycerides as well as macromolecular compounds which consist of ester-forming units (monomers) and form an ester bond-linked polymer.
  • glycolide refers to an ester of any carboxylic acid which may be linear or branched, saturated or unsaturated and optionally substituted with glycerin (propane-1,2,3-triol).
  • the term includes mono-, di- and tri Esters of glycerol, ie one, two or three of the hydroxy groups of glycerol are esterified with one, two or three carboxylic acids.
  • derivative structurally closely related derivatives of a basic chemical structure to understand that have the same structural elements, but carry different substituents.
  • the encapsulating material serves in particular for the protection of the active substance. Accordingly, the encapsulating material preferably exhibits high stability against oxidation.
  • Enzymatically degradable substances are known to the person skilled in the art as substances which are structurally modified by the action of active proteins, so-called enzymes, and degraded as a result of the change. The structural change can either lead directly to a separation of bonds within the degradable substance, or else lead to a structural change designed in such a way that the degradable substance becomes unstable in the given environment, for example in the form that surrounding water on the substance can be degrading.
  • any enzymatically degradable substances except glycerides can be used which have a melting point of at least
  • the enzymatically degradable substances by hydrolases such as esterases (group EC 3.1.1), lipases (EC 3.1.1.3), proteases (group EC 3.4), carbohydrases (glycosidases: group EC 3.2.1), phospholipases (EC 3.1 .1.4, 3.1.1.32, 3.1.4.3, 3.1.4.4), amidases and acylases (group 3.5) degradable, wherein a degradability by lipases and proteases is particularly preferred.
  • hydrolases such as esterases (group EC 3.1.1), lipases (EC 3.1.1.3), proteases (group EC 3.4), carbohydrases (glycosidases: group EC 3.2.1), phospholipases (EC 3.1 .1.4, 3.1.1.32, 3.1.4.3, 3.1.4.4), amidases and acylases (group 3.5) degradable, wherein a degradability by lipases and proteases is particularly preferred.
  • the encapsulation material to be used according to the invention comprises an enzymatically degradable substance, except glycerides, which has a melting point of at least 35 ° C., preferably at least 40 ° C.
  • glycerides which has a melting point of at least 35 ° C., preferably at least 40 ° C.
  • enzymatically degradable substances with the exception of particular interest are glycerides having a melting point in the range from 45 to 100 0 C, particularly preferably 50 to 65 0 C.
  • the encapsulating material may also comprise, as enzymatically degradable substance, mixtures of the abovementioned enzymatically degradable substances.
  • Preferred enzymatically degradable substances are selected from the groups comprising:
  • Simple esters and amides preferably prepared from n-alcohols or n-amines with aliphatic or aromatic, optionally hydroxy-functional carboxylic acids, such as, for example, myristyl myristate,
  • Mono- and polyesters of polyols preferably having 2 to 8 hydroxyl groups (di- to octahydroxy compounds), glycerol being excluded as polyol, such as
  • Ethylene glycol esters propylene glycol esters, sugar esters (mono- and disaccharide esters), sugar alcohol esters, sugar esters, trimethylol esters, pentaerythritol esters, esters of di- or triethanolamine and their alkylene oxide addition products.
  • Besoner's preferred mono- and polyesters of polyols are ethylene glycol distearate, ethylene glycol dihydroxystearate, PEG-3 distearate, polyethylene glycol mono- or distearate, sorbitan stearate, cetearyl glucoside, methyl glucoside stearate, sucrose stearate, glucose pentaacetate, and PEG-40 hydrogenated castor oil.
  • Polyglycerol esters preferably polyglycerol with up to 10 glycerol units, such as, for example, polyglyceryl-3-stearate and polyglycerol-10-stearate,
  • Esters of di- and tricarboxylic acids such as, for example, citrate dilaurate, dicetyl adipate and dicetearyl succinate
  • Phospholipids such as fractions of soy lecithin (phosphatidylcholine, ethanolamine, inositol, and Phosphatidic acid or its lysophospholipids or mixtures of these compounds), in particular hydrogenated lecithin
  • Alkyl carbonates having one or more carbonate groups and one or more alkyl groups such as
  • Amino acid derivatives in the form of esters, amides and peptides such as N-cocoyl glutamate, stearyl pyroglutamate and sodium stearoyl glutamate, silicone esters and silicone ester waxes as described, for example, in US 4,725,658, as well as other organomodified siloxanes with e.g. Amide groups, carbonate groups, peptide chains and sugar groups.
  • Particularly preferred groups from which the enzymatically degradable substances are selected are the groups: simple esters and amides, mono- and polyesters of polyols, phospholipids and amino acids and derivatives, single esters and amides and mono- and polyesters of polyols being very particularly preferred ,
  • the oxidation stability of the enzymatically degradable substances used as encapsulating material depends inter alia on the proportion of unsaturated components (inter alia alcohols or carboxylic acids). The lower this one
  • a preferably used enzymatically degradable substance or a preferably used mixture preferably has an iodine value less than or equal to 50, particularly less than or equal to 20 and particularly preferably less than or equal to 10.
  • the iodine value can be determined in particular according to DIN EN 14111. It may be advantageous for the purposes of the present invention if the encapsulation material comprises as additional component a glyceride having a melting point of at least 35 ° C.
  • the encapsulation material to be used according to the invention can thus be a mixture of at least one enzymatically degradable substance, except glycerides, having a melting point of at least 35 ° C., preferably at least 40 ° C., with at least one glyceride having a melting point of at least 35 ° C., preferably at least 40 ° C. , exhibit.
  • mixtures of at least one enzymatically degradable substance with the exception of glycerides, having a melting point in the range from 45 to 100 ° C., particularly preferably 50 to 65 ° C., with at least one glyceride having a melting point in the range from 45 to 100 0 C, more preferably 50 to 65 0 C has.
  • the glycerides to be used according to the invention as an additional component comprise in particular a glyceride which has a dynamic viscosity in the range from 5 to 200 mPa * s, preferably 10 to 50 mPa * s and particularly preferably 15 to 22 mPa * s at 70 ° C., measured according to DIN EN ISO 3219.
  • two or three of the hydroxyl groups of glycerol may be esterified with two or three carboxylic acids which have 8 to 36, in particular 8 to 30, preferably 12 to 22 and particularly preferably 14 to 20 carbon atoms.
  • carboxylic acids which have 8 to 36, in particular 8 to 30, preferably 12 to 22 and particularly preferably 14 to 20 carbon atoms.
  • triglycerol esters which have three groups derived from Carboxylic acids having 12 to 22, particularly preferably 14 to 20 carbon atoms are derived.
  • Preferred triglycerol esters have, in particular, the formula (I) in which the radicals R 1 , R 2 and R 3 are each independently
  • Hydrocarbon radical having 7 to 35, in particular 7 to 29, preferably 11 to 21 and particularly preferably 13 to 19 carbon atoms.
  • Hydrocarbon radicals in the present case denote in particular saturated and / or unsaturated radicals, which preferably consist of carbon and hydrogen. These radicals can be cyclic, linear or branched. These include in particular alkyl radicals and alkenyl radicals, where the alkenyl radicals may comprise one, two, three or more carbon-carbon double bonds.
  • the preferred alkyl radicals include, in particular, the heptyl, octyl, 1,1,3,3-tetramethylbutyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, Octadecyl, nonadecyl, eicosyl and the cetyleicosyl group.
  • alkenyl radicals having a carbon-carbon double bond examples include the heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, Heptadecenyl, octadecenyl, nonadecenyl, eicosenyl and the cetyleicosenyl group.
  • hydrocarbon radicals set forth above may have substituents and / or heteroatoms. These include in particular groups which comprise oxygen, nitrogen and / or sulfur, such as, for example, hydroxyl groups, thiol groups or amino groups. However, the proportion of these groups should be so low that the properties of the glycerides are not adversely affected.
  • saturated carboxylic acids from which the glycerides are derived include octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid, heptadecanoic acid, octadecanoic acid, eicosanoic acid, docosanoic acid, tetracosanoic acid, hexacosanoic acid octacosanoic acid, triacontanoic acid, tetratriacontanoic acid and pentatriacontanoic acid, more preferably eicosanoic acid and docosanoic acid ,
  • the properties of the glycerides are particularly dependent on the type and amount of fatty acids contained in the glycerides. Accordingly, the proportion of long-chain, saturated fatty acids is very high compared to the proportions present in many naturally occurring oils and fats. According to the invention can be used as an additional component, a monoglyceride obtained by esterification of glycerol with a particularly long-chain fatty acid. Furthermore, as an additional component di- or triglycerides can be used which have a correspondingly high proportion of Carboxylic acids having 12 to 36 and preferably 14 to 20 carbon atoms.
  • triglycerides which have a high content of stearic acid and / or palmitic acid.
  • Triglycerides which are at least 10% by weight, preferably at least 20% by weight and very particularly preferably at least 30% by weight of stearic acid and / or palmitic acid residues, based on the total content of fatty acids, can preferably be used as additional component.
  • triglycerides which comprise stearic acid and palmitic acid groups are used as additional component in particular.
  • the weight ratio of stearic acid to palmitic acid is preferably in the range of 10: 1 to 1: 1, more preferably 4: 1 to 1.5: 1.
  • a triglyceride can be used as an additional component whose fatty acid spectrum is preferably 50 to 90 wt .-%, particularly preferably 60 to 80 wt .-% and most preferably about 70 wt .-% stearic acid and preferably 10 bis 50% by weight, more preferably 20 to 40% by weight and most preferably about 30% by weight of palmitic acid.
  • the oxidation stability of the glycerides used as an additional component is dependent inter alia on the proportion of unsaturated carboxylic acids. The lower this proportion, the higher the oxidation stability.
  • a preferred glyceride to be used as an additional component preferably has an iodine value of less than or equal to 50, more particularly less than or equal to 20 and particularly preferably less than or equal to equal to 10. The iodine value can be determined in particular according to DIN EN 14111.
  • these glycerides can also be obtained from natural sources, in particular from plants.
  • triglycerides can be used as an additional component, which are commercially available from Evonik Goldschmidt GmbH, Essen under the trade name Tegin®.
  • suitable triglycerides can be used, which are available from the company. Cognis GmbH & Co. KG under the name Edenor®, in particular Edenor® NHTi V can be used.
  • the glyceride to be used according to the invention as an additional component differs from the active substances to be released.
  • the drugs to be released are susceptible to oxidation or otherwise unstable.
  • the glyceride to be used as an additional component of the drug can be distinguished by the oxidation sensitivity, which can be determined, for example, by the iodine value (grams of iodine which can be attached to the double bonds of 100 g of drug substance).
  • the iodine value grams of iodine which can be attached to the double bonds of 100 g of drug substance.
  • preparations whose active ingredient has an iodine value which is at least 5 greater than the iodine value of the glyceride to be used as the encapsulating material.
  • this iodine number difference is at least 10, more preferably at least 20.
  • the molecular weight of the preferred glycerides to be used as an additional component is not critical per se.
  • glycerides are often with a molecular weight in the range of 200 to 1600 g / mol, preferably 400 to 1500 g / mol and particularly preferably 500 to 1200 g / mol.
  • the proportion of enzymatically degradable substance, excluding glycerides, or the mixture based on the weight of the preparation is preferably in the range of 1 to 99.5 wt .-%, particularly preferably 10 to 80 wt .-% and most preferably 20 to 70% by weight.
  • the encapsulation material additionally comprises a polymer comprising polyester units.
  • polymer with polyester units in the context of the present invention refers to a macromolecular compound which consists of ester-forming units (monomers) and forms a polymer linked via ester bonds, in particular units derived from diols and dicarboxylic acids and units which The proportion of units which can form polyesters based on the weight of the polymer is preferably at least 10% by weight, particularly preferably at least 30% by weight.
  • the polymer with polyester units has a melting temperature of at least 30 0 C, preferably at least 35 0 C.
  • a melting temperature range from 30 0 C to 90 0 C, particularly preferably from 35 0 C to 70 0 C and most preferably from 40 0 C to 65 0 C.
  • the melting temperature can be determined by differential scanning Calometry (DSC) can be determined, for example with the apparatus Mettler DSC 27 HP and a heating rate of 10 ° C / min.
  • the polymer contained in the encapsulating material with polyester units has a viscosity in the range of 50 mPa * s to 250 Pa * s, preferably in the range of 100 mPa * s to 100 Pa * s and particularly preferably in the range of 200 mPa * s to 10 Pa * s, this size being measured by means of rotational viscometry at 110 ° C.
  • the measurement can be carried out according to DIN EN ISO 3219 at 30 s "1 , for which example two 20 mm plates can be used.
  • the acid number of the polymer with polyester units is preferably in the range of 0 to 20 mg KOH / g, more preferably in the range of 1 to 15 mg KOH / g and most preferably in the range of 6 to 10 mg KOH / g. This property can be measured by titration with NaOH (see DIN 53402).
  • polyester units which have a hydroxyl number in the range from 0 to 200 mg KOH / g, preferably in the range from 1 to 150 mg KOH / g and most preferably in the range from 10 to 140 mg KOH / g. This property is measured according to ASTM E222.
  • the molecular weight of the polymer with polyester units is not critical per se, but the viscosities set out above must be maintained. Depending on the structure of the polymer, this may have a relatively high molecular weight.
  • the polymer may have a molecular weight in the range of 1000 g / mol to 400000 g / mol, preferably 1500 to 100000 g / mol and very particularly preferably 1800 to 20,000 g / mol. This size refers to the weight average molecular weight (Mw) which can be measured by gel permeation chromatography, measured in DMF and as a reference
  • the molecular weight of the polymers to be used according to the invention can be determined from the acid and the hydroxyl number, if the components are known. This method is particularly suitable for small molecular weight polymers.
  • preferred polymers may have a molecular weight determined from the acid and the hydroxyl number in the range from 1000 to 30 000 g / mol, preferably 1500 to 15 000 g / mol.
  • the polymer with polyester units may, for example, have a linear structure. To comply with the parameters set out above, these polymers often have a relatively low molecular weight, preferably in the
  • Dynacoll® 7362 is a polyester having a hydroxyl number in the range of 47 to 54, a molecular weight of about 2000 g / mol, a melting point of 53 0 C and a viscosity of 0.5 Pa * s, measured at 80 0 C by means of rotational viscometry.
  • the molecular weight of Dynacoll® 7362 can be determined in particular from the acid and the hydroxyl number.
  • encapsulating materials which, in addition to at least one enzymatically degradable substance, excluding glycerides, or the mixture additionally comprise at least one hyperbranched polymer which has a hydrophilic core with polyester units and hydrophobic end groups.
  • the encapsulation process can be carried out with significantly reduced amounts of solvents or compressed gases.
  • the hyperbranched polymer can thus itself as
  • Solvent / dispersant act The resulting reduced solvent / gas concentrations lead to safer processes compared to the prior art because hyperbranched polymers can not form explosive vapors like other prior art solvents.
  • Preferred preparations include a hyperbranched polymer having a hydrophilic core.
  • Hydrophilic means that the core is capable of absorbing a high level of water.
  • the hydrophilic core is soluble in water.
  • the solubility in water at 90 0 C is at least 10 percent by mass, more preferably at least 20 percent by mass. This size is measured on the basis of the hyperbranched polymer before the hydrophobization, ie on the hydrophilic core as such. The measurement can be carried out according to the so-called piston method, wherein the water solubility of the pure substance is measured.
  • the substance (solids must be pulverized) is dissolved in water at a temperature slightly above the test temperature.
  • the solution is cooled and held at the test temperature.
  • the solution is stirred until the equilibrium is reached.
  • the measurement can be performed immediately at the test temperature, if it is ensured by appropriate sampling that the saturation equilibrium is reached.
  • the concentration of the test substance in the aqueous solution, which must not contain undissolved substance particles determined by a suitable analysis method.
  • the hydrophilic core preferably has a front of
  • This property is measured according to ASTM E222.
  • the polymer is reacted with a defined amount of acetic anhydride. Unreacted acetic anhydride is hydrolyzed with water. Then the mixture is titrated with NaOH. The hydroxyl number results from the difference between a comparative sample and the value measured for the polymer.
  • the number of acid groups of the polymer is taken into account.
  • the hyperbranched polymer has a core comprising polyester units.
  • Hyperbranched polymers with polyester units are set forth in particular in EP 0 630 389.
  • the hydrophilic core has a central moiety derived from an initiator molecule having at least 2, preferably at least 3 hydroxy groups, and repeating units derived from monomers having at least one carboxyl group and at least 2 hydroxy groups.
  • the hyperbranched polymers can be obtained by polycondensation, starting from a polyhydric alcohol, first the carboxylic acid groups of the monomers are reacted. This ester groups are formed. Since the monomers comprise at least 2 hydroxy groups, the macromolecule has more hydroxyl groups after each reaction than before the reaction.
  • the initiator molecule is an aliphatic polyol, preferably having 3, 4, 5, 6, 7 or 8, more preferably 3, 4 or 5 hydroxy groups.
  • the initiator molecule is particularly preferably selected from ditrimethylolpropane, ditrimethylolethane, dipentaerythritol, pentaerythritol, alkoxylated pentaerythritol, trimethylolethane, trimethylolpropane, alkoxylated trimethylolpropane, glycerol, neopentyl alcohol,
  • the repeating units are derived from monomers having a carboxyl group and at least 2 hydroxy groups.
  • monomers having a carboxyl group and at least 2 hydroxy groups include in particular dimethylpropionic acid, ⁇ , ⁇ -bis (hydroxymethyl) butyric acid, ⁇ , ⁇ , ⁇ -tris (hydroxymethyl) acetic acid, ⁇ , ⁇ -bis (hydroxymethyl) valeric acid, ⁇ , ⁇ -bis (hydroxy) propionic acid and / or 3, 5-dihydroxybenzoic acid.
  • the hydrophilic core is obtainable by polymerization of dimethylolpropionic acid, particular preference being given to using ditrimethylolpropane, trimethylolpropane, ethoxylated pentaerythritol, pentaerythritol or glycerol as initiator molecule.
  • the hydrophilic core preferably has a molecular weight of at least 1500 g / mol, preferably at least 2500 g / mol.
  • This size refers to the weight average molecular weight (Mw), which by means of
  • the hydrophilic core may have a glass transition temperature which is in the range of -40 to 60 0 C, more preferably 0 to 50 0 C and most preferably 10 to 45 0 C.
  • the glass transition temperature can be determined by DSC method with a heating rate of 3 ° C / min (DMA Tan ⁇ peak, Netsch DMA 242 3-point bending IHz 3 ° C / min).
  • the hydrophobization of the surface of the polymer is generally obtained as the last reaction step by reacting at least a portion of the free hydroxy groups with preferably a long-chain carboxylic acid.
  • the degree of functionalization of the hyperbranched core molecule with hydrophobic end groups, preferably with building blocks containing fatty acid, is preferably at least 5%, particularly preferably at least 30%, particularly preferably at least 40%. According to another aspect of the present invention is the
  • the degree of functionalization refers to the proportion of hydroxyl groups which is converted during the hydrophobization. Accordingly, the degree of functionalization or the degree of esterification with fatty acids can be determined via the measurement of the hydroxyl number for the hyperbranched core molecule before the hydrophobization reaction and after the hydrophobization reaction.
  • the hyperbranched polymer has hydrophobic end groups.
  • hydrophobic end groups means that at least a part of the chain ends of the hyperbranched polymer has hydrophobic groups. It can be assumed hereby that an at least partially hydrophobized surface is obtained in this way.
  • hydrophobic is known per se in the art, wherein the groups, which are present at least at a part of the ends of the hyperbranched polymers, considered by themselves, have a low water solubility.
  • the surface is hydrophobized by groups derived from carboxylic acids having at least 6, preferably at least 12 carbon atoms.
  • the carboxylic acids preferably have at most 40, especially at most 32 carbon atoms, more preferably at most 22 carbon atoms and most preferably at most 18 carbon atoms.
  • the groups can be derived from saturated and / or unsaturated fatty acids.
  • the proportion of carboxylic acids is 12 to 18
  • Carbon atoms at least 30 wt .-%, more preferably at least 50 wt .-% and most preferably at least 60 wt .-%, based on the weight of the carboxylic acids used for the hydrophobization.
  • fatty acids contained in linseed, soybeans and / or tall oil are particularly suitable.
  • fatty acids which have a low content of double bonds for example hexadecenoic acid, in particular palmitoleic acid, and octadecenoic acid, in particular oleic acid.
  • Preferred carboxylic acids in this case have a melting point of at least 35 ° C., preferably at least 40 ° C., and particularly preferably at least 60 ° C. Accordingly, preference is given to using linear, saturated carboxylic acids.
  • octanoic acid include in particular octanoic acid,
  • Decanoic acid dodecanoic acid, tetradecanoic acid, hexadecanoic acid, heptadecanoic acid, octadecanoic acid, eicosanoic acid, docosanoic acid and tetracosanoic acid.
  • Particularly preferred are saturated fatty acids having 16 to 22 carbon atoms, more preferably 16 to 18 carbon atoms.
  • hyperbranched polymers which have a molecular weight of at least 3000 g / mol, preferably at least 6000 g / mol, more preferably at least 7500 g / mol.
  • the molecular weight is at most 30,000 g / mol, more preferably at most 25,000 g / mol.
  • This size refers to the weight average molecular weight (Mw) which can be measured by gel permeation chromatography, measured in DMF and as a reference
  • the polydispersity Mw / Mn of preferred hyperbranched polymers is preferably in the range of 1.01 to 6.0, more preferably in the range of 1.10 to 5.0, and most preferably in the range of 1.2 to 3.0, wherein the Number average molecular weight (Mn) can also be obtained by GPC.
  • the weight ratio of hydrophilic core to hydrophobic end groups may preferably be in the range of 10: 1 to 1:10, more preferably 1: 1 to 1: 2.5. This ratio is calculated from the weight average of the hydrophilic core and the weight average of the hyperbranched polymer.
  • the degree of branching of the hyperbranched polymer is in the range of 20 to 70%, preferably 25 to 60%.
  • the degree of branching is dependent on the components used for the preparation of the polymer, in particular of the hydrophilic core, and on the reaction conditions.
  • the degree of branching can be determined according to Frey et al. This method can be determined in D.Hölter, A. Burgath, H.Frey, Acta Polymer, 1997, 48, 30 and H. Magnusson, E. Malmström,
  • the hyperbranched polymer preferably has a melting temperature of at least 30 0 C, more preferably at least 35 0 C and most preferably at least 40 ° C.
  • the melting point of the hyper-branched polymer may be at most 60 0 C, particularly preferably at most 57 0 C and most preferably at most 55 ° C, preferably at most 65 0 C is particularly preferred.
  • the melting temperature can be determined by means of differential scanning calometry (DSC), for example with the apparatus Mettler DSC 27 HP and a heating rate of 10 ° C / min.
  • the water solubility of the hyperbranched polymer after the hydrophobization is preferably at most 10% by mass, more preferably at most 7% by mass, and most preferably at most 5 Percent by mass, measured according to the previously described piston method at 40 0 C.
  • the hyperbranched polymer consists essentially of hydrogen, oxygen and carbon.
  • the term essentially means that further elements up to at most 10 wt .-%, particularly preferably at most 5 wt .-% are contained in the hyperbranched polymer.
  • the hyperbranched polymer can be enzymatically degraded. This can be achieved, for example, by virtue of the hydrophilic core and / or the hydrophobic shell comprising enzymatically degradable organic ester groups.
  • hyperbranched polymers The preparation of these hyperbranched polymers is set forth in particular in EP 0 630 389.
  • an initiator molecule can be reacted with at least one compound comprising at least 2 hydroxy groups and at least one carboxylic acid group.
  • a hydrophilic core is obtained which can be reacted with at least one hydrophobic compound, for example a long-chain carboxylic acid.
  • reaction is carried out at a temperature in the
  • Methanesulfonic acid trifluoroacetic acid, BF 3 , AlCl 3 and SnCl 4 ; Titanium compounds, in particular tetrabutyl titanate; Zinc and / or tin powder.
  • water released during the esterification is removed from the reaction mixture.
  • the proportion of polymer with polyester units is preferably in the range from 1 to 98.5% by weight, more preferably in the range from 10 to 90% by weight and most preferably in the range from 20 to 80% by weight .-%.
  • the weight ratio of polymer to polyester units to enzymatic degradable substance, excluding glycerides, or to the mixture is not critical per se. Surprisingly, however, the proportion of active ingredient can be increased by a high proportion of polymer, so that the degree of loading can be increased surprisingly by this measure. On the other hand, the storage stability as well as the enzymatic degradability can be improved by the use of a high proportion of enzymatically degradable substance, excluding glycerides, or to mixture.
  • preparations characterized by a weight ratio of polymer to polyester units to enzymatically degradable substance, excluding glycerides, or to the mixture, preferably in the range from 20: 1 to 1:20, more preferably from 10: 1 to 1 : 10 and most preferably 5: 1 to 1: 5.
  • the preparations according to the invention comprise at least one active substance.
  • the active ingredient is preferably connected by a non-covalent manner with the encapsulating material. This can be done for example by ionic or polar interactions or by van der Waals forces. Due to the interaction of encapsulating material and active ingredient, the preparation of the present invention may differ from a conventional mixture of these components.
  • This interaction can be measured in a known manner.
  • spectroscopic methods are often suitable for this purpose. For example, partial shifts in the infrared spectrum can be observed.
  • the preparations according to the invention can show, compared with a conventional mixture, a delayed release of the active substance into a medium which is different from the active ingredient of the preparation.
  • the sustained release may be carried out according to the method described by Smirnova, I. ; Suttiruengwong, S .; ArIt, W. "Feasibility Study of Hydrophilic and Hydrophobic Silica Aerogels as Drug Delivery Systems”; Journal of Non-Crystalline Solids (2004) 54-60.
  • the time difference to obtain an identical concentration of the drug in the medium into which the drug is released is at least 1 minute, preferably at least 5 minutes.
  • this time difference refers to the measurement of a preparation of the present invention and the measurement of a conventional mixture of these components under identical sustained release conditions. Delayed release means that the conditions are not chosen so that the drug releases the drug as quickly as possible. These conditions are familiar to those skilled in the knowledge of this application.
  • the values The conventional mixture can also be determined by separate addition of the components.
  • the preparation is preferably encapsulated, with the term "encapsulation" being known in the art
  • the active agent can be embedded, for example, in a sheath comprising the encapsulation material a matrix encapsulation, wherein the
  • Encapsulating material protects the active ingredient in a matrix.
  • the active ingredient is homogeneously dispersed in the encapsulating material.
  • the matrix forms a uniform phase together with the active ingredient, so that the active ingredient in the
  • Encapsulating material is present dissolved.
  • the protection of the active ingredient can be carried out by a matrix encapsulation and / or a core-shell encapsulation.
  • the preparations according to the invention may be in the form of microcapsules or microparticles.
  • microcapsules means particles and aggregates which contain an inner space or core which is filled with a solid, gelled, liquid or gaseous medium and enclosed by a continuous shell of encapsulation material. These particles are preferably small in size.
  • the microscopic capsules may have one or more nuclei in continuous
  • Encapsulating material consisting of one or more layers, distributed.
  • the distribution of enveloping material can go so far that a homogeneous mixture of sheath and core material is formed, which is referred to as a matrix.
  • Matrix systems are also known as microparticles.
  • the preparation of the present invention may be particulate.
  • these particles preferably have a size in the range from 1 to 1000 .mu.m, more preferably 10 to 500 .mu.m.
  • the shape of the particles is not critical per se, but the particles preferably have a spherical shape.
  • spherical in the context of the present invention means that the particles preferably have a spherical shape, it being obvious to the person skilled in the art that particles of a different shape may also be present due to the production methods, or that the shape of the particles may deviate from the ideal spherical shape ,
  • the term spherically means that the ratio of the largest dimension of the particles to the smallest extent is at most 4, preferably at most 2, these dimensions being measured in each case by the center of gravity of the particles.
  • at least 70%, more preferably at least 90%, based on the number of particles, are spherical.
  • the particle size can be determined in a well-known manner. For example, this can be done microscopic images can be used, which can be evaluated visually and / or with the help of computers.
  • preferred microparticles have a particularly narrow particle size distribution.
  • at least 80 wt .-% of the particles are within a size range of 1 .mu.m to 200 .mu.m, preferably 1 .mu.m to 100 .mu.m, more preferably 1 .mu.m to 50 .mu.m.
  • preferably 90% of the particles have a size in the range of 1 to 1000 ⁇ m, more preferably 3 to 800 ⁇ m, more preferably 7 to 700 ⁇ m and most preferably 10 to 500 ⁇ m.
  • Preferred preparations according to the present invention show a well controllable enzymatic degradability.
  • preparations which can be degraded within three days or less, preferably 2 days or less and more preferably of one day or less.
  • at least 20% by weight, particularly preferably at least 50% by weight of the active substance contained in the preparation is released on contact of the preparation with an enzyme within not more than three days, preferably within not more than two days and most preferably within 24 hours ,
  • preparations are degraded with a suitable enzyme, in particular a lipase, for example Lipomod® 34P (Biocatalyst Lmt., UK).
  • a suitable enzyme in particular a lipase
  • preparations with a degree of loading of 1 to 20 wt .-% can be examined, wherein preferably 1 wt .-% loaded with active ingredient polymer particles in 50 ml of phosphate buffer (pH 5.01) or in 50 ml solution of the enzyme Lipomod® 34P (Biocatalyst Lmt., UK) in the same buffer (with a concentration of Lipomod® 34P of 0.5 mg / ml) can be suspended.
  • the samples can be kept in a water bath at 37 ° C without mixing.
  • samples of about 5 ml can be taken, the concentration of the active ingredient with suitable methods, such as iodometric titration with Metrohm Titroprocessor 686, can be analyzed.
  • suitable methods such as iodometric titration with Metrohm Titroprocessor 686.
  • the release of a comparative sample, which does not comprise enzyme is taken into account in order to exclude problems of storage stability under the selected measurement conditions, so that the previously stated value results on the difference between the measured sample and the comparative sample.
  • the preparations of the present invention can exhibit excellent shear stability, which can be greatly influenced by the choice of encapsulating material and process conditions in preparation of the preparation.
  • the preparations show a shear stability of 1 minute or longer, preferably 5 minutes or longer, this stability being determined at a load equivalent to that of an ULTRA-TURRAX® stirrer at 15,000 revolutions per minute, preferably 20,000 revolutions per minute.
  • a dispersion of the particles for example in a pharmaceutical oil (Paraffin OiI WINOG 100 Pharma from Univar GmbH), is prepared in this case, it being possible for the dispersion to comprise, for example, 10% by weight of the preparation.
  • the particles are before and after the stability measurement, which can be carried out for example by a ULTRA-TURRAX® stirrer at 15,000 revolutions per minute, preferably 20,000 revolutions per minute, examined microscopically, whereby the particle shape, size and distribution is assessed. Shear stability under the aforementioned conditions is given if no significant changes can be observed.
  • the storage stability of the preparations according to the invention is often surprisingly high, depending on the nature and composition of the medium, if the preparations are stored in the form of dispersions or emulsions, and / or the storage temperatures.
  • preferred preparations may be stored for a long period of time, for example, 10 days or longer, preferably 30 days or longer, and more preferably 90 days or longer. This size can be measured by the release of drug into a medium or the degradation of the drug. In this case, these data relate to the period up to which at most 10% of the active ingredient were released into a medium in which the preparation can be stored or the time to which not more than 10% of the active ingredient, for example, were degraded by oxidation.
  • the active substance encompassed by the encapsulating material is preferably a pharmaceutical or cosmetic active substance, in particular a bioactive natural substance.
  • bioactive natural product includes substances which have an effect on biological systems and can be obtained from natural sources, in particular from plants or animals.
  • the bioactive natural substance preferably has a molar mass in the range from 50 g / mol to 100000 g / mol, more preferably 100 g / mol to 5000 g / mol and very particularly preferably 160 g / mol to 1500 g / mol.
  • the bioactive natural substance can be selected from a wide range, with particular preference being given to natural substance extracts, in particular phytotextracts.
  • Natural substance extracts are substances or mixtures of substances which can be obtained by extraction of natural substances, whereby phytoe extracts are obtained from plants. Natural extracts are usually subjected to no chemical conversion, but only by physical processes, including extraction, distillation and precipitation methods derived from natural products. Therefore, such substances are in great demand in the cosmetic and pharmaceutical industry due to high consumer acceptance.
  • Preferred natural product extracts include compositions obtained by extraction from fruit components (kernels, peel, juices) such as e.g. of pineapple, apple, banana, pear, strawberry, grapefruit, peach, apricot, apricot, pomegranate, cranberry, cranberry, cherry, raspberry, currant, coffee, mango, oranges, passion fruit, sour cherry, grapes, quince, soy, Olives, cocoa, nut or blackthorn but also from plant components (leaves, woods, roots) such as from vanilla, chamomile, coffee, tea, oak, incense or spices or from products of fruit components (kernels, peel, juices) such as e.g. of pineapple, apple, banana, pear, strawberry, grapefruit, peach, apricot, apricot, pomegranate, cranberry, cranberry, cherry, raspberry, currant, coffee, mango, oranges, passion fruit, sour cherry, grapes, quince, soy, Olives
  • Extracts Food industry such as rum, beer, cognac, tequila, brandy, whiskey, coffee oil and malt are obtained. These extracts can often be obtained commercially. These include in particular Cocoa Absolute 14620, Cocoa LC 10167, Cocoa P 11197, Cocoa U88; all available from Degussa GmbH. Natural extracts are extracts that can be obtained from natural sources or have properties that are similar to these extracts.
  • the preferred bioactive natural substances include in particular flavorings, flavorings, natural extracts, enzyme-modified food additives, natural waxes, proteins, peptides, vitamins and vitamin precursors, fats and fatty acids, amino acids and amino acid precursors, for example creatine, sugar and sugar derivatives, nucleotides, nucleic acids and Precursors and derivatives thereof, for example, DNA and RNA oligomers, drugs, enzymes and coenzymes.
  • bioactive natural products containing at least one compound selected from the group consisting of tocopherol and derivatives, ascorbic acid and derivatives, deoxyribonucleic acid, retinol and derivatives, alpha-lipoic acid, niacinamide, ubiquinone, bisabolol, allantoin, phytantriol, panthenol, AHA Acids, amino acids, hyaluronic acid, polyglutamic acid, beta-glucans, creatine and creatine derivatives, guanidine and guanidine derivatives, ceramides,
  • Sphingolipids phytosphingosine and phytosphingosine derivatives, sphingosine and sphingosine derivatives, sphinganine and sphinganine derivatives, pseudo-ceramides, essential oils, peptides, proteins, protein hydrolysates, plant extracts and vitamin complexes.
  • Derivatives of the substances set out above are, in particular, compounds which have a substantially similar effect as the respective substance per se. In many cases, organisms can Convert derivatives into the appropriate substance, so that by these derivatives a similar effect is achieved as by administration of the respective substance.
  • Coenzyme Q10 (2, S-dimethoxy- ⁇ -methyl- ⁇ -polyprenyl-1-benzoquinone) belongs in particular to the preferred coenzymes.
  • the vitamins include, in particular, vitamin A, vitamins of the B complex, for example vitamin B1, vitamin B2, vitamin B3 (folic acid) and vitamin B12, vitamin C.
  • the preferred amino acids include in particular DL-methionine, L-lysine, L-threonine, L-tryptophan, L-theanine and L-leucine.
  • the flavoring agents include in particular alkanes, alkenes, ketones, aldehydes, sulfur-containing compounds, heterocycles, carboxylic esters, alcohols and / or natural extracts, for example limonene or linalool.
  • oils are, in particular, oils derived from animal or vegetable material and which can be used in the present invention are olive oil, palm oil, rapeseed oil, flax oil and seeds oils of e.g. Sunflower, apple, pear, citrus, like
  • Particularly preferred oils are in particular core oils.
  • Nuclear oils can be extracted in particular from the seeds or seeds of plants, in which case residues from the processing of fruits and berries and particularly preferably from juice production are particularly suitable.
  • residues from the processing of e.g. Apple, peach, pear, citrus fruits such as tangerine, orange, grapefruit or lemon, melon, pumpkin, raspberry, blackberry, elderberry, cherry, rosehip, apricot, strawberry, currant and pomegranate are suitable as starting materials.
  • Processes for obtaining preferred oils from plant constituents by extraction are known, in particular, from the document DE-A-10 2005 037 209.
  • Nuclear oils often have a high content of triglycerides of unsaturated fatty acids. Thus, the proportion of oleic acid and / or linoleic often 50 to 90 wt .-%.
  • core oils are rich in vitamins, such as vitamin A and / or minerals.
  • flavonoids such as resveratrol and xantuhomol
  • isoflavonoids terpenes
  • phytosterols such as beta-sitosterol
  • glycoconjugates such as aloeresin, aloenin
  • triterpenoids such as 11-keto-ß-boswellic acid or acetyl-11-keto-ß -boswellic acid which can be obtained from frankincense
  • polyphenols in particular lupeol, squalene, hydroxytyrosol, Tocopherols and vanilin be used as a bioactive natural substance.
  • natural waxes are examples of preferred natural products. These waxes are mostly of plant or animal origin, which represent typical natural products. A strict delimitation of the vegetable and animal waxes due to the fatty acids and fatty alcohols involved in their construction can not be made. However, it is undeniable that montanic acid, palmitic acid and stearic acid are typical fatty acids involved in this natural growth. Cetyl alcohol and ceryl alcohol should be mentioned here on the side of the alcohols. Real natural waxes of plant origin are, for example.
  • Palm leaf waxes such as carnauba wax, palm wax, raffia wax, ouricoury wax, grass waxes, such.
  • Berry and fruit waxes are, for example, apple wax, pear wax, quince wax, Japan wax,
  • Bayberry wax and myrtle wax The most well-known example of a genuine natural wax of animal origin is the beeswax, which consists mainly of palmitic acid, ie a palmitic acid esterified with miricyl alcohol. Also known are Chinese insect waxes, shellac wax and wool waxes, as they can be obtained, for example, from sheep's wool. Processes for obtaining preferred waxes from plant constituents by extraction are known, in particular, from the document DE-A-10 2005 037 210.
  • the active ingredients set forth above can be used alone or as a mixture of two, three or more. In this case, the mixtures may comprise active substances of the same class or of different classes. For example, a combination may comprise a mixture comprising one or more fruit waxes and / or one or more core oils.
  • the preparations according to the invention can have a surprisingly high proportion of active ingredients.
  • the weight ratio of encapsulating material to active ingredient may preferably be in the range from 40: 1 to 0.5: 1, more preferably in the range from 20: 1 to 2: 1.
  • the degree of loading may preferably be in a range from 1% to 95%, particularly preferably 5% to 90%, more preferably 10 to 60% and very particularly 10 to 30%, the degree of loading being given by the proportion by weight of the active substance in the total weight of the preparation is.
  • the active ingredient can be released from the preparation according to the invention per se in any desired manner.
  • enzymatic degradation may occur to liberate the substance to be released.
  • the release period can be controlled by the degradation rate.
  • the release can be selectively controlled by changing the pH, temperature, pH, radiation frequency and type of medium.
  • the type of medium can be changed, for example, by the addition of solvents, surfactants or salts.
  • a solvent for the variation of the medium can under other water or alcohols, such as ethanol or isopropanol.
  • the release rate can be controlled by the proportion of polymer with polyester units.
  • the degree of functionalization of the hyperbranched polymer or the hydroxyl number of the polymer are parameters that can be used to control the release.
  • the release of active ingredient can be controlled, in particular, via the proportion of encapsulating material which protects the active ingredient and / or the degree of functionalization / degree of hydrophobization or the hydroxyl number of the polymer with polyester units.
  • the release period is greater, the higher the proportion of encapsulating material in the preparation.
  • concentration in the starting mixture also exceeds the polymer concentrations of 10% by mass which are customary in the prior art a polymer concentration of 70 mass percent can be increased.
  • concentration of enzymatically degradable substance, excluding glycerides, or on the mixture and on polymer decides together with the temperature control or the change of pH or solvent power of the solvent on the proportion of encapsulating material and thus on the release time.
  • the low molecular weight compounds for the preparation of the preparations according to the invention, the low molecular weight compounds and the
  • Encapsulating material are combined.
  • Various methods in particular RESS, GAS, PCA, SEDS and / or PGSS methods are suitable for this purpose. Such methods are well known in the art and described, for example, in Gamse et al. , Chemical Engineer Technology 77 (2005), No. 6, pages 669-679.
  • This method consists of a microencapsulation of active ingredients in particle form by spraying an inert supercritical carrier gas together with the coating material for the active ingredients in a high-pressure fluidized bed in an autoclave, which is characterized in that simultaneously active ingredients in the form of an aqueous solution through the carrier gas in the high-pressure fluidized bed with be sprayed. This produces particles with an average particle size of about 20 to 1,000 microns and with a
  • the invention thus provides a process for the preparation of the preparations according to the invention, characterized in that the active substance in a fluidized bed operated with supercritical gases with a mixture of at least one polymer with polyester units with at least one enzymatically degradable substance, excluding glycerides, having a melting point of at least 35 ° C. or with one
  • Polymer with polyester units at least one enzymatically degradable substance, excluding glycerides, having a melting point of at least 35 ° C. or a mixture of at least one enzymatically degradable substances having a melting point of at least 35 ° C. with at least one glyceride having a melting point of at least 35 ° C.
  • microparticles with a predetermined particle size and particle size distribution can be obtained by the method according to the invention.
  • the process is particularly flexible. So can be made with a system both small and large particles with a relatively narrow particle size distribution.
  • microparticles can be formed which have powdery and / or liquid active ingredients.
  • the active ingredients may also be soluble in the encapsulating material or may be a solvent for the encapsulating material.
  • the process can be carried out at relatively low temperatures, so that temperature-sensitive active ingredients can be encapsulated.
  • the process of the present invention can be carried out at a high throughput, so that large quantities of particles can be formed in a short time.
  • the particles can be formed continuously.
  • the systems for carrying out the method according to the invention in this case generally require only very low investment and operating costs, since the systems can also be operated at atmospheric pressure and in many cases no explosive mixtures are formed, wherein in In general, the use of hazardous substances can be dispensed with. In operation, the plants generally require only small amounts of energy. In addition, the systems often have a low complexity, so that the maintenance costs are low and the systems can be easily and safely controlled.
  • a melt which comprises at least one polymer with polyester units, at least one enzymatically degradable substance, excluding glycerides, having a melting point of at least 35 ° C. or a mixture of at least one enzymatically degradable substances having a melting point of at least 35 0 C with at least one glyceride having a melting point of at least 35 0 C and at least one active ingredient.
  • the active ingredient is preferably dispersed in the melt comprising the enzymatically degradable substance, excluding glycerides, or the mixture and the polymer with polyester units.
  • agitators such as agitators, a stirred tank with propeller, disc, pulley, anchor, helical, blade, vane, inclined blade, cross blade, screw, MIG®, INTERMIG® -, ULTRA-TURRAX®, screw, tape, finger, basket, impeller stirrer, as well as
  • Dispersers and homogenizers which can work with ultrasound among others, are used.
  • the devices may generally comprise at least one shaft, to which in turn preferably 1 to 5 stirring elements may be attached.
  • a solution, a suspension or a dispersion arise, wherein the particle size of the distributed phase present preferably at most 5000 microns, more preferably at most 1000 microns, if the active ingredient is particulate.
  • the stirring speed may be in the range of 10 to 25,000 revolutions per minute, more preferably in the range of 20 to 20,000 revolutions per minute.
  • the temperature at which the melt is produced may also be in a wide range depending, inter alia, on the solidification temperature of the polymer with polyester units or the enzymatically degradable substance, with the exception of glycerides, or the mixture.
  • the temperature is in the range of 40 0 C to 200 ° C, more preferably in the range of 45 ° C to 100 0 C.
  • the pressure used in preparing the melt is also not critical, this often depends on the nature of the bioactive agent and the Solidification temperature of the encapsulation material is dependent. For example, the pressure in the range of 0.1 mbar to 200 bar, preferably in the range of 10 mbar to 100 bar can be selected.
  • a solvent is understood as meaning a substance in which the encapsulation material is soluble and which has to be separated off during the production process, since this compound is not present in the preparations, especially the microparticles should be included.
  • active ingredients outlined above may have the properties of a solvent. However, these substances are a desired constituent of the microcapsules, so that these compounds are not a solvent in the context of the present invention. Accordingly, the use of solvent to carry out the process is not necessary. On the other hand, some active ingredients are supplied in dissolved form, with the used
  • Solvents are generally not critical for use of the active ingredient, so that they are, for example, safe for health. Such adjuvants need not necessarily be separated prior to the production of the melt. Rather, these auxiliary substances can be incorporated into the melt.
  • the melt described above is converted into a second liquid phase in which the encapsulation material is sparingly soluble and which has a solidification temperature below the solidification temperature of the encapsulation material.
  • the second liquid phase comprises one or more substances which are immiscible with the encapsulating material and which are referred to as
  • the second liquid phase is preferably hydrophilic.
  • the term “poorly soluble” means that the solubility of the encapsulating material in the second liquid phase should be as low as possible depending on the temperature. Accordingly, the dispersing conditions can often be chosen so that the smallest possible proportion of the encapsulating material is dissolved in the second liquid phase.
  • the encapsulating material in particular the polymer with
  • the encapsulating material may preferably have a solubility by the piston method at 40 ° C of at most 20 mass% in the second liquid phase.
  • the second liquid phase has a solidification temperature below the
  • Solidification temperature of the encapsulation material results from the melting temperature or the glass transition temperature of the main component of the second liquid phase, wherein freezing point reductions can occur by auxiliaries or additives or by the use of mixtures of substances.
  • This size can be obtained from DSC measurements, wherein the melting points or freezing points of the usual main components of the second liquid phase are listed in reference books.
  • hydrophilic substances which may be contained as the main component in the second liquid phase include, in particular, water and alcohols having 1 to 7, preferably
  • the second liquid phase may comprise, in addition to the main component, additional auxiliaries, in particular dispersants and stabilizers.
  • auxiliaries are known in the art, with dispersants counteracting aggregation of the particles.
  • the preferred surfactants include in particular anionic surfactants such as lauryl ether sulfate, cationic surfactants and nonionic surfactants such as polyvinyl alcohols and ethoxylated fatty alcohols.
  • Stabilizers can be used for a variety of applications, with these adjuvants maintaining or stabilizing a desirable, unstable state. These include, in particular, antisettling agents, such as pectins and / or carrageenan.
  • the second liquid phase preferably comprises 60 to 100% by weight of the main constituent, for example the hydrophilic substances set out above, such as water or alcohols having up to 4 carbon atoms. Furthermore, the second liquid phase may contain 0 to 40 wt .-% auxiliary substances, in particular 0 to 20 wt .-% emulsifiers and 0 to 20 wt .-% stabilizers.
  • the melt introduced into the second liquid phase is dispersed at a temperature which is greater than or equal to the solidification temperature of the encapsulating material.
  • the solidification temperature of the encapsulation material denotes the temperature at which the encapsulation material solidifies, so that particles no longer agglomerate to form larger aggregates without external influences at this temperature.
  • the solidification temperature can be given, for example, by the glass transition temperature or the melting temperature of the polymer with polyester units or the enzymatically degradable substance, with the exception of glycerides, or the mixture determined, for example, by DSC (differential scanning calorimetry) methods can be.
  • amorphous polymers generally have only a glass transition temperature, whereas crystalline polymers exhibit a melting temperature.
  • Partly crystalline polymers can exhibit both a glass transition temperature and a melting temperature, in which case the temperature at which the particles show no agglomeration is decisive. If the surface is essentially crystalline, the melting point of these components is critical.
  • Dispersing in this context means that the melt comprising at least one active substance is finely dispersed in the continuous second liquid phase.
  • the dispersing may in this case with known devices and devices, such as agitators, a stirred tank with propeller, disc, pulley, anchor, helical, blade, vane, inclined blade,
  • the devices may generally comprise at least one shaft, to which in turn preferably 1 to 5 stirring elements may be attached.
  • the duration and the energy input of the dispersion are dependent on the desired particle size and particle size distribution. Accordingly, the duration of dispersing can be selected in a wide range. Preferably, the dispersing is for a
  • Duration in the range of 1 second to 5 hours, more preferably carried out in the range of 10 seconds to 2 hours.
  • the dispersing number of Newton may preferably be in the range of 0.1 to 1000, more preferably in the range of 0.4 to 800.
  • the Reynolds number in the dispersion may preferably be in the range from 1 to 10 7 , particularly preferably in the range from 10 to 10 6 .
  • the stirring speed may be in the range of 10 to 25,000 revolutions per minute, more preferably in the range of 20 to 10,000 revolutions per minute.
  • the Newton number or the stirring speed used depends on the desired particle size and particle size distribution. The more energy is supplied and the longer it is dispersed, the smaller particle sizes can be achieved. A narrow particle size distribution can also be achieved by a high dispersion energy and a long dispersion time. On the other hand, long dispersion times and high dispersing energies are often associated with additional costs.
  • the temperature at which the melt is dispersed in the second liquid phase may also be within a wide range, including but not limited to Solidification temperature of the encapsulation material is dependent.
  • the temperature is in the range of 40 0 C to 200 ° C, more preferably in the range from 45 to 100 0 C.
  • the pressure used in dispersing the melt is likewise not critical, and this in many cases on the nature of the active ingredient and the solidification temperature of the encapsulating material is dependent.
  • the pressure in the range of 10 mbar to 200 bar preferably in the range of 100 mbar to 100 bar are selected.
  • the temperature when dispersing is greater than or equal to the solidification temperature of the encapsulating material.
  • the dispersion temperature is from 1 0 C to 100 0 C, more preferably 5 0 C to 70 0 C and most preferably 10 to 50 0 C above the
  • the weight ratio of melt to the second liquid phase can be in a wide range. Preferably, this ratio is in the range of 1: 1 to 1: 200, more preferably 1: 1.5 to 1:10.
  • the composition may comprise, for example, 50 to 99% by weight, preferably 70 to 98% by weight of second liquid phase and 1 to 50% by weight, preferably 2 to 30% by weight of melt.
  • the dispersed melt is solidified.
  • the solidification can be carried out by known methods, for example by adding salts at a temperature slightly above the solidification temperature or by cooling.
  • the solidification of the Melting by cooling the second liquid phase to a temperature below the solidification temperature of the encapsulating material.
  • the type of cooling depends, among other things, on the desired particle size and particle size distribution. Among other things, rapid cooling can lead to a particularly uniform particle size distribution and small particles, since aggregation can be avoided. In this case, the formation of agglomerates is lower with a large cooling volume.
  • the particle size distribution and the size of the particles can be influenced by auxiliaries, for example dispersants and emulsifiers. These additives may for example be added to the second phase, wherein an additive of the surface of the particles formed can be achieved. This additization may also reduce aggregation of the microparticles during drying or storage.
  • auxiliaries for example dispersants and emulsifiers.
  • additives may for example be added to the second phase, wherein an additive of the surface of the particles formed can be achieved. This additization may also reduce aggregation of the microparticles during drying or storage.
  • composition thus obtained can be further processed directly, without a
  • the present method may comprise the step of separating the microparticles formed in the second liquid phase.
  • the separation can be carried out by known methods, in particular by filtration, centrifuging, sedimentation, magnetic separation, flotation, sieving or decanting, which methods can be used individually or in combination.
  • the compounds of the second liquid phase substantially completely are separated so that dried microparticles are obtained or the particles can be concentrated.
  • the devices which can be used for separating or concentrating the microparticles are generally known.
  • centrifuges, decanters, centrifugal separators, filters such as gravity filters, suction filters (vacuum filters), pressure filters, suction-pressure filters, press filters, vacuum drum filters, belt filters, disc filters, plan filter, chamber filter press, frame filter press, candle filter, leaf filter, membrane filter plate and / or belt presses are used.
  • the temperature at separation or concentration may also be in a wide range, depending among other things on the solidification temperature of the encapsulating material.
  • the chosen temperature should be below the solidification temperature of the encapsulant.
  • the temperature is in the range of -20 0 C to 80 0 C, more preferably in the range of -10 0 C to 40 0 C.
  • the pressure used in the separation or concentration is also not critical, this often depends on the nature of the active ingredient and the solidification temperature of the encapsulation material is dependent. For example, the pressure in the range of 10 mbar to 200 bar, preferably in the range of 100 mbar to 100 bar are selected.
  • the particles obtained can be washed.
  • Washing liquid can be treated to separate additive residues and / or active substances, which is located on the surface of the particles from the particles. Accordingly, the particles, especially the
  • Encapsulating material should not be soluble in the washing liquid.
  • the substance to be separated off for example the active substance should have the highest possible solubility.
  • Washing liquids include in particular water and / or alcohols having 1 to 7, preferably 1 to 4
  • Carbon atoms in particular methanol, ethanol, propanol and / or butanol. These liquids can be used individually or as a mixture of two, three or more liquids.
  • the temperature during washing can also be in a wide range, which depends inter alia on the solidification temperature of the encapsulating material. To avoid aggregation of the particles, the chosen temperature should be below the
  • Solidification temperature of the encapsulating material lie.
  • the temperature is in the range of -20 0 C to 100 0 C, more preferably in the range of -10 0 C to 40 ° C.
  • the pressure used during washing is also not critical, and this is often dependent on the nature of the active ingredient and the solidification temperature of the encapsulating material.
  • the pressure during washing can be selected in the range from 10 mbar to 200 bar, preferably in the range from 100 mbar to 100 bar.
  • the devices useful for washing the particles are well known.
  • devices can be used which comprise a mixing vessel and a separator.
  • the mixing vessels preferably comprise the above-described devices and devices for dispersing.
  • the microparticles obtained can be dried.
  • the devices useful for drying the microparticles are well known. For example, drum dryers, tumble dryers, plate dryers, screw dryers, paddle dryers, cylinder dryers, drum dryers, freeze dryers, fluidized bed dryers, spray dryers, dryers, grinding dryers, hop dryers,
  • Tunnel dryer vacuum dryer and / or vacuum contact dryer can be used.
  • the temperature during drying can also be in a wide range, this among others from the
  • Solidification temperature of the encapsulation material is dependent. To avoid aggregation of the particles, the chosen temperature should be below the
  • Solidification temperature of the encapsulating material lie.
  • the temperature during drying in the range from -20 0 C to 50 0 C, more preferably in the range of - 10 ° C to 30 ° C.
  • the pressure used during drying is also not critical, and this is often dependent on the nature of the bioactive agent and the solidification temperature of the encapsulation material.
  • the pressure in the range of 0.1 mbar to 10 bar, preferably in the range of 0.2 mbar to 2 bar are selected.
  • the method described above can be carried out with simple systems that can be constructed from components known per se. Suitable plants preferably comprise at least two mixing vessels and a separator, wherein the mixing vessels are connected to one another via at least one feed and the second mixing vessel is connected to the separator. The separated in the separator second phase can preferably be recycled via a return in a mixing vessel.
  • a pump in the conduit between the first mixing vessel in which the melt is prepared, and the second mixing vessel in which the melt is dispersed in the second liquid phase, a pump may be provided which is highly viscous
  • the preferred pumps include in particular screw pumps, for example screw pumps with one, two or three screws; Screw compressors, vane pumps, rotary lobe pumps, rotary pumps, piston pumps, rotary lobe pumps and / or peristaltic pumps.
  • the plant preferably has at least three mixing vessels, wherein at least two mixing vessels are connected via feeds to at least one mixing vessel.
  • at least one mixing vessel for producing the melt at least one mixing vessel for producing the second liquid phase and at least one mixing vessel for dispersing the melt in the second liquid phase are used.
  • the melt and the second liquid phase can be batchwise or in further separate mixing vessels be continuously prepared to ensure a continuous production of microparticles.
  • the mixing vessels used in the plant for the production of preparations according to the invention can be equipped to be tempered. Accordingly, these mixing vessels may comprise heating elements or cooling elements.
  • the plant may comprise at least one dryer which is connected to the separator.
  • the plant may preferably comprise a device for washing particles.
  • the solidification of the melt in the dispersion can be achieved in the system via various measures.
  • the mixing vessel in which the dispersion has been prepared can be cooled. This can be done for example by external cooling or by supplying liquids, which preferably has the same or a similar composition as the second liquid phase.
  • a heat exchanger or heat exchanger, a mixing valve or an additional mixing vessel can be used for this purpose.
  • the system may include pumps, for example, for the transport of liquids or for generating over° Can serve negative pressure. Suitable pumps are dependent on the respective purpose.
  • the preferred pumps include, for example, positive displacement pumps, such as pumping stations, screw conveyors, bellows pumps, piston pumps,
  • Rotary piston pumps external / internal gear pumps, diaphragm pumps, rotary vane pumps, centrifugal pumps, peristaltic pumps, toothed belt pumps, eccentric screw pumps, Screw pumps and screw compressors and / or hydraulic rams;
  • Flow pumps such as a centrifugal pump, axial pump, diagonal pump and / or radial pump; Bubble Pump, Water Jet Pump, Steam Jet Pump, Ram (Hydraulic Ram),
  • Vacuum pumps such as positive displacement pump, propellant pump, molecular pump, turbomolecular pump, cryopump, sorption pump, oil diffusion pump.
  • FIG. 1 describes a first embodiment of a plant for carrying out the process of the present invention.
  • Figure 2 describes a second embodiment of a plant for carrying out the process of the present invention.
  • Figure 3 describes a third embodiment of a plant for carrying out the process of the present invention.
  • FIG. 4 describes a fourth embodiment of a plant for carrying out the process of the present invention.
  • Figure 5 describes a fifth embodiment of a plant for carrying out the process of the present invention.
  • FIG. 1 shows a first embodiment of a plant for carrying out the process of the present invention.
  • This plant may comprise, for example, one, two or more feeds 1 or 2, for example lines or feed screws, containing one or more polymers with polyester units, one or more enzymatically degradable substances, excluding glycerides, or the mixture of at least one enzymatically degradable substance at least one glyceride and / or one or more active ingredients are fed to a first mixing vessel 3.
  • the supplied substances can be converted into a melt comprising at least one polymer with polyester units, at least one enzymatically degradable substance, excluding glycerides, or the mixture of at least one enzymatically degradable
  • Substance comprising at least one glyceride and at least one active ingredient.
  • the components can be finely dispersed.
  • a solution, a dispersion or suspension can be produced.
  • the encapsulating material forms the
  • Matrix phase in which the active substance is distributed For this purpose, the devices described above can be used.
  • the melt obtained in mixing vessel 3 can be transferred, for example with a pump 4 via the feed 5, for example, a line in the mixing vessel 6.
  • the mixing vessel 6 can have one, two, three, four or more further feeds 7, 8, 9, 10, for example lines or feed screws, via which, for example, stabilizers, emulsifiers, hot water and / or cold water can be supplied.
  • water used as an example as a second liquid phase.
  • any other compound previously described as a major constituent of the second liquid phase may also be employed in lieu of or in conjunction with water.
  • the water thus serves merely as an example of the compounds set forth above, which can be replaced accordingly by the other substances.
  • the feeds 7, 8, 9, 10 can all open in the mixing vessel 6. Furthermore, these feeds can also be brought together before entering the mixing vessel 6.
  • a solution can be prepared which comprises, for example, water or ethanol and auxiliaries, for example stabilizers and emulsifiers, as the main constituent.
  • This solution can be heated to a temperature above the solidification temperature of the encapsulant.
  • the supplied components may already have a corresponding temperature.
  • Mixing vessel 6 are supplied. In mixing vessel 6, the melt is dispersed in the solution described above.
  • the mixing vessel 6 known dispersing devices.
  • the devices described above can be used.
  • the mixing vessel 6 can be cooled by means of a cooling medium, which is passed through a heat exchanger or a double jacket.
  • the particles thus obtained can be separated from the second liquid phase.
  • the composition obtained in mixing vessel 6, which has solidified microparticles, for example, be transferred via a line 11 into the separator 13 with a pump 11.
  • the separator 13 serves to separate or concentrate the microparticles contained in the second liquid phase, wherein each of the devices set forth above can be used for this purpose.
  • the microparticles are separated from the second liquid phase in the separator, in many cases a concentration may be sufficient.
  • the separated second liquid phase which may comprise, for example, water, emulsifiers and stabilizers, can be introduced into the mixing vessel 6 via a return line 14, for example a line.
  • the separated microparticles can be transferred, for example, by means of a pump 15 via the feed 16, for example a line, into the dryer 17.
  • a pump 15 via the feed 16, for example a line
  • residues of the second liquid phase such as water can be removed.
  • the dried microparticles can be removed via the line 18 to the dryer.
  • the second embodiment a mixing vessel 3 with feeds 1, 2 for producing a melt, a mixing vessel 6 for
  • the second liquid phase is produced in a further mixing vessel 19, which may have, for example, one, two, three or more feeds 20, 21, 22.
  • a further mixing vessel 19 may have, for example, one, two, three or more feeds 20, 21, 22.
  • the components of the second liquid phase as the main constituent, for example, water or ethanol, and auxiliaries, for example stabilizers and emulsifiers, can be added to the mixing vessel 19.
  • the water or ethanol can be replaced by any of the second liquid phase compounds set forth above, independently of the other components.
  • the solution obtained in mixing vessel 19 can be transferred, for example with a pump 23 via the feed 9, for example, a line in the mixing vessel 6.
  • Cold water or cooled ethanol for example, can be introduced into the mixing vessel 6 via the feed 10 in order to solidify the dispersed melt.
  • the separated in the separator 13 second liquid phase for example, water or ethanol, the may additionally contain excipients, such as emulsifiers or stabilizers, are recycled to the mixing vessel 6.
  • excipients such as emulsifiers or stabilizers
  • the third embodiment also has a mixing vessel 3 with feeds 1, 2 for producing a melt, a mixing vessel 19 for producing the second liquid phase, a mixing vessel 6 for dispersing the melt in a second liquid phase, a separator 13 and a dryer 17 on.
  • the cooling of the melt after dispersing in the second liquid phase is achieved by an external cooling 24, preferably a heat exchanger, provided in line 12 between the mixing vessel 6 and the separator 13.
  • an external cooling 24 preferably a heat exchanger, provided in line 12 between the mixing vessel 6 and the separator 13.
  • the present method can also be carried out continuously. Furthermore, this embodiment can be operated particularly energy-efficient.
  • the fourth embodiment also has a mixing vessel 3 with feeds 1, 2 for producing a melt, a mixing vessel 19 for producing the second liquid phase, a mixing vessel 6 for dispersing the melt in a second liquid phase, a separator 13 and a dryer 17 on.
  • the cooling of the melt after dispersing in the second liquid phase is achieved by supplying a cold liquid via line 25, which substantially corresponds to the composition of the second liquid phase, to the melt solidify.
  • the supply of cold liquid can take place via a mixing valve 26, which is provided in line 12 between the mixing vessel 6 and the separator 13.
  • auxiliaries such as emulsifiers or stabilizers
  • Mixing vessel 6 are introduced, which can not be recovered in the separator 13 back. In this case, this part can be heated to the temperature of the mixing vessel 6. Another part of the separated in the separator 13 second liquid phase can be passed into the conduit 25.
  • the second phase can be cooled, so that the temperature of the second liquid phase introduced into the line 25 corresponds to the temperature of the cold liquid.
  • the present method can also be carried out continuously. Furthermore, this embodiment can be operated particularly energy-efficient.
  • the fifth embodiment also has a mixing vessel 3 with feeds 1, 2 for producing a melt, a mixing vessel 19 for producing the second liquid phase, a mixing vessel 6 for dispersing the melt in a second liquid phase, a separator 13 and a dryer 17 on.
  • the cooling of the melt after dispersing in the second liquid phase is carried out in a mixing vessel 27, wherein the cooling can be achieved for example by supplying a cold liquid, which substantially corresponds to the composition of the second liquid phase, to the melt to solidify.
  • the supply of cold liquid can be made via the line 28.
  • auxiliaries such as emulsifiers or stabilizers
  • this part can be heated to the temperature of the mixing vessel 6.
  • Another part of the separated in the separator 13 second liquid phase can be passed into the conduit 28.
  • the second phase can be cooled, so that the Temperature of the introduced into the supply line 28 second liquid phase corresponds to the temperature of the cold liquid.
  • the present method can also be carried out continuously. Furthermore, this embodiment can be operated particularly energy-efficient.
  • the sixth embodiment also has a mixing vessel 3 with feeds 1, 2 for producing a melt, a mixing vessel 19
  • a mixing vessel 6 for dispersing the melt in a second liquid phase Preparation of the second liquid phase, a mixing vessel 6 for dispersing the melt in a second liquid phase, a separator 13 and a dryer 17 on.
  • the transfer of the composition obtained in the mixing vessel 6 into the mixing vessel 27 can be assisted by a pump 38 which is provided in line 12.
  • the sixth embodiment has a mixing vessel 29, in which the melt can be premixed to ensure a level in mixing vessel 3, which ensures a continuous inflow of melt into the mixing vessel 6.
  • the melt is formed continuously or in batches, wherein in the mixing vessel 29, the encapsulating material and the active ingredient via the feeds 1 and 2 can be supplied.
  • the melt can be transferred with a pump 30 via line 31 into the mixing vessel 3.
  • the second liquid phase can also be preformed in a mixing vessel 32 before the second liquid phase is transferred into the mixing vessel 19. By this measure, it can be ensured that second liquid phase is continuously transferred from the mixing vessel 19 into the mixing vessel 6.
  • the mixing vessel 32 the second liquid phase can be formed continuously or in batches, wherein the components can be introduced into the mixing vessel 32 via the supply lines 33, 34 and 35.
  • the produced second liquid phase can be transferred by a pump 36 via line 37 into the mixing vessel 19.
  • part of the second liquid phase separated in the separator 13 can be passed via the return into the mixing vessel 6 (not shown).
  • this part can be heated to the temperature of the mixing vessel 6 or 32 or 19.
  • Another part of the separated in the separator 13 second liquid phase can be fed into the supply line 28.
  • the second phase can be cooled so that the temperature of the second liquid phase introduced into the feed line 28 corresponds to the temperature of the cold liquid.
  • the sixth embodiment has an apparatus for washing the particles.
  • This device comprises a mixing vessel and a separator, wherein these components can also be accommodated in a housing. Accordingly, the separated in separator 13 particles can be transferred by a pump 39 via feed 40 into a mixing vessel 41, in which the particles can be cleaned with a washing liquid, which is supplied via line 42. With a pump 43, the composition can be transferred via line 44 into a separator 45. In the separator 45, the cleaned particles are separated from the washing liquid.
  • the scrubbing liquid can be recycled and reused, the recirculation 46, depending on the type of scrubbing liquid, both in the line 42 can be recycled (not shown) or in one of the previously used mixing vessels 6, 19, 27 and / or 32, wherein the temperature of the washing liquid can be adjusted respectively.
  • the cleaned particles can be transferred by means of pump 47 via feed 48 into the dryer 17. Due to this particular embodiment, the present method can also be carried out continuously. Furthermore, this embodiment can be operated particularly energy-efficient. In addition, particles with a particularly favorable and controllable release profile can be obtained.
  • compositions according to the invention can be used, for example, in cosmetics, in particular in cosmetic formulations for the surface treatment of skin and skin appendages, in hairsprays, in deodorants, in perfumes and in
  • Cosmetic wipes in medicines, in phase change materials, in wellness products, in foods, in feeds, in beverages, in moisturizing compositions, such as emollients and / or moisturizers, in phytonutrients, in controlled odorant release compositions, and / or in packaging become.
  • moisturizing compositions such as emollients and / or moisturizers, in phytonutrients, in controlled odorant release compositions, and / or in packaging become.
  • emollients is in itself widespread and generally refers to a cosmetic oil that is given a moisturizing property. Such oils are sometimes used to treat dry skin.
  • Phytonutrients are understood in particular to be plant-based food additives which have advantageous effects. These food additives may include, for example, the carotenoids set forth above,
  • Flavonoids Flavonoids, phytosterols and / or polyphenols.

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Polymers & Plastics (AREA)
  • Food Science & Technology (AREA)
  • Nutrition Science (AREA)
  • Mycology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Birds (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Emergency Medicine (AREA)
  • Dermatology (AREA)
  • Zoology (AREA)
  • Dispersion Chemistry (AREA)
  • Botany (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une préparation comprenant un matière d'encapsulation et au moins un principe actif qui peut être libéré de la préparation de façon contrôlée. La préparation selon l'invention est caractérisée en ce que la matière d'encapsulation comprend au moins une substance enzymatiquement dégradable, à l'exception de glycérides, présentant un point de fusion d'au moins 35°C et en outre au moins un polymère à unités polyester. Le polymère à unités polyester présente une température de fusion d'au moins 30°C et une viscosité comprise entre 50 mPa*s et 250 Pa*s, mesurée à l'aide d'un viscosimètre rotatif à 110 °C.
PCT/EP2009/061379 2008-10-17 2009-09-03 Préparations pour une libération contrôlée de principes actifs WO2010043446A2 (fr)

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DE102008042923.6 2008-10-17
DE102008042923A DE102008042923A1 (de) 2008-10-17 2008-10-17 Präparate zur gesteuerten Freisetzung von Wirkstoffen

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WO2010043446A3 WO2010043446A3 (fr) 2010-06-10

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